A Review on Hepatotoxic Effects of Methotrexate Therapy with Possible Strategies that May Counteract Hepatotoxicity

Main Article Content

Mohammed J Manna
Murtadha S Jabur
Atheer S. Alsabah
Luma Saad Baqir

Abstract

Methotrexate, inhibitor of a dihydrofolate reductase, is a chemotherapeutic treatment applied in many kinds of tumors as an anti-metabolite. also, Methotrexate applied to treat different other disorders, including diseases of autoimmunity, such as psoriasis, rheumatism, vasculitis and ulcerative colitis and Crohn’s disease. However, Methotrexate induces toxic effects on neurons, kidney toxicity, and liver damage, also Methotrexate have been associated with elevation risk of hepatic injury, fibrosis and cirrhosis. Methotrexate work as a dihydrofolic acid analog that binds to the dihydrofolate reductase enzyme that prevent the synthesis of tetrahydrofolic acid,  that is essential synthesis of DNA. Although folic acid combine with Methotrexate therapy to prevent hepatotoxic effects, folic acid  may reduce therapeutic effects of Methotrexate so recent research focus incorporation of new agent to counteract Methotrexate induced hepatotoxicity that include vitamin B12, vitamin E,  N-acetylcysteine, melatonin, Erdosteine, inulin, Ferulic acid, Human placental extract, Natural plant extract (flavonoids). These agents are promising to counteract Methotrexate induced hepatotoxicity.


Materials and methods: A comprehensive literature review on different published articles hepatotoxic effects of methotrexate and   was carried out by electronic research on Medline, PubMed, Google scholar, and Cochrane Libran data bases using different searching terms related to prevention of methotrexate induced hepatotoxicity. The article focusses on clinical studies   in different regions in the period of 2018-2022.


Objective: To search for new update modality preventive therapy for methotrexate induced liver damage Results: Recent study oriented for the prevention and treatment of   methotrexate associated with hepatotoxicity.

Article Details

How to Cite
Mohammed J Manna, Murtadha S Jabur, Atheer S. Alsabah, & Luma Saad Baqir. (2023). A Review on Hepatotoxic Effects of Methotrexate Therapy with Possible Strategies that May Counteract Hepatotoxicity. International Journal of Medical Science and Clinical Research Studies, 3(06), 1090–1094. https://doi.org/10.47191/ijmscrs/v3-i6-10
Section
Articles

References

I. Ayad MW, El Naggar AA, El Naggar M. MTHFR C677T polymorphism: association with lymphoid neoplasm and effect on methotrexate therapy. Eur J Haematol. 2014;93:63–69. doi: 10.1111/ejh.12302.

II. Sakthiswary R, Suresh E. Methotrexate in systemic lupus erythematosus: a systematic review of its efficacy. Lupus. 2014;23:225–235. doi: 10.1177/0961203313519159.

III. Roenigk HH, et al. Methotrexate in psoriasis: consensus conference. J Am Acad Dermatol. 1998;38:478–485. doi: 10.1016/S0190-9622(98)70508-0.

IV. Fournier MR, et al. Changes in liver biochemistry during methotrexate use for inflammatory bowel disease. Am J Gastroenterol. 2010;105:1620–1626. doi: 10.1038/ajg.2010.21.

V. Xu P, et al. The efficacy and safety of methotrexate in refractory Crohn's disease. Zhonghua Nei Ke Za Zhi. 2014;53:188–192.

VI. Buizer AI, et al. Behavioral and educational limitations after chemotherapy for childhood acute lymphoblasticleukemiaorWilmstumor. Cancer. 2006;106:2067–2075. doi: 10.1002/cncr.21820.

VII. Abd El-Twab SM, et al. 18 β-Glycyrrhetinic acid protects against methotrexate-induced kidney injury by up-regulating the Nrf2/ARE/HO-1 pathway and endogenous antioxidants. Ren Fail. 2016;38:1516–1527. doi: 10.1080/0886022X.2016.1216722.

VIII. Mahmoud AM, et al. Methotrexate hepatotoxicity is associated with oxidative stress, and down-regulation of PPARγ and Nrf2: protective effect of 18β-glycyrrhetinic acid. Chem Biol Interact. 2017;270:59–72. doi: 10.1016/j.cbi.2017.04.009.

IX. .methotrexate-induced liver injury. J Gastroenterol Hepatol. 2001;16:1395–1401. doi: 10.1046/j.1440-1746.2001.02644.x.

X. Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials. Arthritis Rheum. 1992;35:1117–1125. doi: 10.1002/art.1780351003.

XI. Rau R, Karger T, Herborn G, Frenzel H. Liver biopsy findings in patients with rheumatoid arthritis undergoing longterm treatment with methotrexate. J Rheumatol. 1989;16:489–493.

XII. Adams LA, Angulo P. Treatment of non-alcoholic fatty liver disease. Postgrad Med J. 2006;82:315–322. doi: 10.1136/pgmj.2005.042200.

XIII. Walker TM, Rhodes PC, Westmoreland C. The differential cytotoxicity of methotrexate in rat hepatocyte monolayer and spheroid cultures. Toxicol In Vitro. 2000; 14:475–485. doi: 10.1016/S0887-2333(00)00036-9.

XIV. Yeo CM, Chong VH, Earnest A, Yang WL. Prevalence and risk factors of methotrexate hepatoxicity in Asian patients with psoriasis. World J Hepatol. 2013;5(5):275. doi: 10.4254/wjh.v5.i5.275

XV. Allen LH, Miller JW, de Groot L, Rosenberg IH, Smith AD, Refsum H, et al. Biomarkers of Nutrition for Development (BOND): vitamin B-12 review. J Nutr. 2018;148(suppl_4):1995S–2027S.

XVI. Mechie N.C., Goralzcyk A.D., Reinhardt L., Mihm S., Amanzada A., Association of serum vitamin B12 levels with stage of liver fibrosis and treatment outcome in patients with chronic hepatitis C virus genotype 1 infection: a retrospective study. BMC Res Notes. 2015; 8 (1) : 260 .

XVII. Derya Karabulut, Emel Ozturk, Nurhan Kuloglu, Ali Tuğrul Akin, Emin Kaymak & Birkan Yakan . Effects of vitamin B12 on methotrexate hepatotoxicity: evaluation of receptor-interacting protein (RIP) kinase. Naunyn-Schmiedeberg's Archivesof Pharmacology volume 393, pages2473–2480 (2020).

XVIII. S. Nemmiche, D. Chabane-Sari, P. Guiraud. Role of alpha-tocopherol in cadmium-induced oxidative stress in Wistar rat’s blood, liver and brain. Chem. Biol. Interact., 170 (3) (2007), pp. 221-230.

XIX. Shahramian I et al. Accelerating Effects of Vitamin E Supplementation on Liver Enzyme Normalization in Children with Acute Hepatitis A Infection; a Single-Blinded Clinical Trial. Archives of Clinical Infectious Diseases.2020;15:(6) e100591

XX. Binit Vaidya, Manisha Bhochhibhoya, and Shweta Nakarmi. Efficacy of Vitamin E in Methotrexate-Induced Hepatotoxicity in Rheumatoid Arthritis: An Open-Label Case-Control Study. Int J Rheumatol. 2020 1. doi: 10.1155/2020/5723485; 2020: 5723485.

XXI. Tuba Demirci, Semin Gedikli, Nurinnisa Ozturk, Nevra Aydemir Celep. The Protective Effect of N-acetylcysteine Against Methotrexate-Induced Hepatotoxicity in Rat. EJMI 2019;3(3):219–226.

XXII. Ayat O.S.Montasser,HananSaleh, Omar A.Ahmed-Farid,AidaSaad and Mohamed-Assem S.Marie. Protective effects of Balanites aegyptiaca extract, Melatonin and Ursodeoxycholic acid against hepatotoxicity induced by Methotrexate in male rats. Asian Pacific Journal of Tropical Medicine. Volume 10, Issue 6, June 2018; 10: 557-565.

XXIII. R.J. Reiter. Interactions of the pineal hormone melatonin with oxygen-centered free radicals: a brief review. Braz Med Biol Res, 26 (11) (1993), pp. 1141-1155

XXIV. M.A. Eghbal, A. Eftekhari, E. Ahmadian, Y. Azarmi, A. Parvizpur. A Review of Biological and Pharmacological Actions of Melatonin: Oxidant and Pro-oxidant Properties. J Pharma Reports, 1 (1) (2016), pp. 1-9

XXV. K.A. Marshall, R.J. Reiter, B. Poeggeler, O.I. Aruoma, B. Halliwell. Evaluation of the antioxidant activity of melatonin in vitro Free Radical Biol Med, 21 (3) (1996), pp. 307-315

XXVI. E. Sewerynek, R.J. Reiter, D. Melchiorri, G.G. Ortiz, A. Lewinski. Oxidative damage in the liver induced by ischemia-reperfusion: protection by melatonin Hepatogastroenterology, 43 (10) (1996), pp. 898-905

XXVII. Saritas A, Kandis H, Baltaci D, Yildirim U, Kaya H, Karakus A, Colakoglu S, Memisogullari R, Kara IH. Nacetyl cysteine and erdosteine treatment in acetaminophen-induced liver damage. Toxicol Ind Health 2014; 30(7): 670-678.

XXVIII. Akbulut S. Cytoprotective effects of amifostine, ascorbic acid and n-acetylcysteine against methotrexate-induced hepatotoxicity in rats. World J Gastroenterol 2014; 20(29): 10158-10165.

XXIX. 29. Helvaci R, Koc A, Kozlu T, Kaya H, Sogüt S. Effects of erdosteine on acetaminophen-induced hepatotoxicity in rats. Toxicol Pathol 2008; 36(5): 714-719.

XXX. Osama Abdelaziz Hassan, Entesar Farghally Amin, Rabab Ahmed Moussa. Protective effect of erdosteine against methotrexateinduced hepatotoxicity in rats. Tropical Journal of Pharmaceutical Research July 2020; 19 (7): 1465-1471.

XXXI. Heibatullah Kalantar ,Nooshin Asadmasjedi,Mohammad rezaAbyaz MasoudMahdavinia,Narges Mohammad. Protective effect of inulin on methotrexate- induced liver toxicity in mice. Biomedicine & Pharmacotherapy February 2019;110: 943-950.

XXXII. .Graf E. Antioxidant potential of ferulic acid. Free Radic Biol Med. 1992;13(4):435–448. doi:10.1016/0891-5849(92)90184-I

XXXIII. Deuster P, Maier S, Moore V, Paton J, Simmons R, Vawter K. Dietary Supplements and Military Divers: A Synopsis for Undersea Medical Officers. Uniformed Services Univ of The Health Sciences Bethesda Md Dept Of Military; 2004.

XXXIV. Ronchetti D, Borghi V, Gaitan G, Herrero JF, Impagnatiello F. NCX 2057, a novel NO‐releasing derivative of ferulic acid, suppresses inflammatory and nociceptive responses in in vitro and in vivo models. Br J Pharmacol. 2009;158(2):569–579. doi:10.1111/j.1476-5381.2009.00324.x.

XXXV. .Zhao Z, Moghadasian MH. Chemistry, natural sources, dietary intake and pharmacokinetic properties of ferulic acid: a review. Food Chem. 2008;109(4):691–702. doi:10.1016/j.foodchem.2008.02.039.

XXXVI. Uehara Y, Kitamura N . Hepatocyte growth factor/scatter factor and the placenta. Placenta.1996; 17:97–101.

XXXVII. Saito S, Sakakura S, Enomoto M, Ichijo M, Matsumoto K, Nakamura T. Hepatocyte growth factor promotes the growth of cytotrophoblasts by the paracrine mechanism. J Biochem.1995; 117:671–676.

XXXVIII. Hofmann GE, Scott RT Jr, Bergh PA, Deligdisch L. Immunohistochemical localization of epidermal growth factor in human endometrium, decidua, and placenta. J Clin Endocrinol Metab.1991; 73:882–887.

XXXIX. Lysiak JJ, Han VKM, Lala PK. Localization of transforming growth factor in the human placenta and decidua: role in trophoblast growth. Biol Reprod.1993; 49:885–894.

XL. Watanabe S et al.L-tryptophan as an antioxidant in human placenta extract. J Nutr Sci Vitaminol.2002; 48:36–39

XLI. Jung J et al.Epigenetic alterations of IL-6/STAT3 signaling by placental stem cells promote hepatic regeneration in a rat model with CCl4-induced liver injury. Int J Stem Cellsw.2015; 8:79–89.

XLII. Chatterjee P et al. Human placenta-derived stromal cells decrease inflammation, placental injury and blood pressure in hypertensive pregnant mice. Clin Sci (Lond).2016; 130:513–523.

XLIII. Mamdooh G ,Mohamed S.A. Human placental extract ameliorates methotrexate-induced hepatotoxicity in rats via regulating antioxidative and anti-inflammatory responses. Cancer Chemotherapy and Pharmacology.2021; 88: 961–971 .

XLIV. F Sahindokuyucu-Kocasari, Y Akyol, and S Garli. Apigenin alleviates methotrexate-induced liver and kidney injury in mice. Human and Experimental Toxicology.2021;40:1721-1731.

XLV. Goudarzi M, Basir Z, Malayeri A, Nesari A and Zaeemzadeh N. Zingerone Attenuates Methotrexate-Induced Hepatotoxicity in Rats. Jundishapur J Nat Pharm Prod. 2022; 17(3): e118745.

XLVI. Yanaşoğlu E et al. Silibinin Effect on Methotrexate-Induced Hepatotoxicity in Rats. Eurasian J Med 2022; 54: 264-269.

XLVII. Ebrahimi R, Reza Sepand M, Afshin Seyednejad S, Omidi A, Akbariani M, Gholami M, and Sabzevari O. Ellagic acid reduces methotrexate-induced apoptosis and mitochondrial dysfunction via up-regulating Nrf2 expression and inhibiting the IĸBα/NFĸB in rats. DARU Journal of Pharmaceutical Science. 2019; 27(2): 721–733.

XLVIII. Elsawy H, Algefare A, Alfwuaires M, Khalil M, Omar M. Elmenshawy, Sedky A, and Abdel-Moneim A. Naringin alleviates methotrexate-induced liver injury in male albino rats and enhances its antitumor efficacy in HepG2 cells. Bioscience Report.2020;26: BSR20193686.